This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Muscular dystrophies are due to genetic defects in components of glycoprotein complexes that attach muscle cells to the extracellular matrix (ECM). For example, Duchenne muscular dystrophy (DMD) is caused by a lack of dystrophin, a linker protein that connects the critical dystrophin-glycoprotein complex (DGC) of the plasma membrane (sarcolemma) to the actin cytoskeleton. Dystrophin deficiency results in increased endocytosis and degradation of the entire DGC from the sarcolemma. This results in reduced ECM binding, membrane damage, unregulated Ca++ flux, and defects in Akt signaling. Notably, dystrophin deficiency in DMD is partially compensated by utrophin, a homolog of dystrophin normally found at the neuromuscular junction (NMJ);the utrophin-glycoprotein complex (UGC) restores some DGC functions, including ECM binding and resistance to contraction-induced cell injury. Aberrant glycosylation is well known to be both a cause and an effect of various types of muscular dystrophies, a group of debilitating and often fatal illnesses. The major plasma membrane glycoprotein of the DGC/UGC that binds to laminin and agrin in the extracellular matrix is [unreadable]-dystroglycan ([unreadable]-DG). [unreadable]-DG bears conventional N- and O-linked glycans and also O-mannosyl residues that can be elongated by a variety of glycosyltransferases. Mutations in several enzymes involved in O-mannosyl biosynthesis, such as POMGnT1, result in muscular dystrophy, demonstrating the critical role of these unique glycans in muscle physiology. In addition, [unreadable]-DG is modified by the like-acetylglucosaminyltransferase (LARGE), a glycosyltransferase that adds a unique phosphate-containing glycan to glycan cores of the protein. Mutations in Large also result in muscular dystrophy further supporting the critical role of specific glycans in muscle cell physiology.